{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T20:38:58Z","timestamp":1792442338753,"version":"4.5.0"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"1","content-domain":{"domain":["eje.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,7]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      Nicotinamide nucleotide transhydrogenase (\n                      <jats:italic>NNT<\/jats:italic>\n                      ), one of the several genes recently discovered in familial glucocorticoid deficiencies (FGD), is involved in reactive oxygen species detoxification, suggesting that extra-adrenal manifestations may occur, due to the sensitivity to oxidative stress of other organs rich in mitochondria. Here, we sought to identify\n                      <jats:italic>NNT<\/jats:italic>\n                      mutations in a large cohort of patients with primary congenital adrenal insufficiency without molecular etiology and evaluate the degree of adrenal insufficiency and onset of extra-adrenal damages.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Sanger or massive parallel sequencing of\n                      <jats:italic>NNT<\/jats:italic>\n                      and patient monitoring.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Homozygous or compound heterozygous\n                      <jats:italic>NNT<\/jats:italic>\n                      mutations occurred frequently (26%, 13 unrelated families, 18 patients) in our cohort. Seven new mutations were identified: p.Met337Val, p.Ala863Glu, c.3G&gt;A (p.Met1?), p.Arg129*, p.Arg379*, p.Val665Profs*29 and p.Ala704Serfs*19. The most frequent mutation, p.Arg129*, was found recurrently in patients from Algeria. Most patients were diagnosed belatedly (8\u201318 months) after presenting severe hypoglycemia; others experiencing stress conditions were diagnosed earlier. Five patients also had mineralocorticoid deficiency at onset. One patient had congenital hypothyroidism and two cryptorchidism. In follow-up, we noticed gonadotropic and genitalia impairments (precocious puberty, testicular inclusions, interstitial Leydig cell adenoma, azoospermia), hypothyroidism and hypertrophic cardiomyopathy. Intrafamilial phenotype heterogeneity was also observed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      <jats:italic>NNT<\/jats:italic>\n                      should be sequenced, not only in FGD, but also in all primary adrenal insufficiencies for which the most frequent etiologies have been ruled out. As NNT is involved in oxidative stress, careful follow-up is needed to evaluate mineralocorticoid biosynthesis extent, and gonadal, heart and thyroid function.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1530\/eje-16-0056","type":"journal-article","created":{"date-parts":[[2016,4,29]],"date-time":"2016-04-29T21:50:19Z","timestamp":1461966619000},"page":"73-84","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":75,"title":["NNT mutations: a cause of primary adrenal insufficiency, oxidative stress and extra-adrenal defects"],"prefix":"10.1093","volume":"175","author":[{"given":"Florence","family":"Roucher-Boulez","sequence":"first","affiliation":[{"name":"1Molecular Endocrinology and Rare DiseasesLyon University Hospital, Bron, France"},{"name":"2Claude Bernard Lyon 1 UniversityLyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delphine","family":"Mallet-Motak","sequence":"additional","affiliation":[{"name":"1Molecular Endocrinology and Rare DiseasesLyon University Hospital, Bron, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinane","family":"Samara-Boustani","sequence":"additional","affiliation":[{"name":"3Pediatric Endocrinology, Gynecology and DiabetologyNecker University Hospital, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Houweyda","family":"Jilani","sequence":"additional","affiliation":[{"name":"1Molecular Endocrinology and Rare DiseasesLyon University Hospital, Bron, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asmahane","family":"Ladjouze","sequence":"additional","affiliation":[{"name":"4Pediatric DepartmentBab El Oued University Hospital, Alger, Algeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre-Fran\u00e7ois","family":"Souchon","sequence":"additional","affiliation":[{"name":"5Pediatric Endocrinology and DiabetologyAmerican Memorial Hospital, Reims, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Simon","sequence":"additional","affiliation":[{"name":"6Pediatric EndocrinologyRobert Debr\u00e9 Hospital, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvie","family":"Nivot","sequence":"additional","affiliation":[{"name":"7Department of PediatricsRennes Teaching Hospital, Rennes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudine","family":"Heinrichs","sequence":"additional","affiliation":[{"name":"8Pediatric EndocrinologyQueen Fabiola Children\u2019s University Hospital, Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryline","family":"Ronze","sequence":"additional","affiliation":[{"name":"9Endocrinology DepartmentL.-Hussel Hospital, Vienne, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xavier","family":"Bertagna","sequence":"additional","affiliation":[{"name":"10Endocrinology DepartmentCochin University Hospital, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laure","family":"Groisne","sequence":"additional","affiliation":[{"name":"11Endocrinology DepartmentLyon University Hospital, Bron-Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Leheup","sequence":"additional","affiliation":[{"name":"12Paediatric and Clinical Genetic DepartmentNancy University Hospital, Vandoeuvre les Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Naud-Saudreau","sequence":"additional","affiliation":[{"name":"13Pediatric Endocrinology and DiabetologyBretagne Sud Hospital Center, Lorient, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilles","family":"Blondin","sequence":"additional","affiliation":[{"name":"13Pediatric Endocrinology and DiabetologyBretagne Sud Hospital Center, Lorient, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Lefevre","sequence":"additional","affiliation":[{"name":"14Pediatric EndocrinologyJeanne de Flandre Hospital, Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laetitia","family":"Lemarchand","sequence":"additional","affiliation":[{"name":"15Pediatric DepartmentLa Rochelle-R\u00e9-Aunis Hospital Group, La Rochelle, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yves","family":"Morel","sequence":"additional","affiliation":[{"name":"1Molecular Endocrinology and Rare DiseasesLyon University Hospital, Bron, France"},{"name":"2Claude Bernard Lyon 1 UniversityLyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","reference":[{"key":"2016060718390495000_175.1.73.1","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1001\/archpedi.1959.02070010156002","article-title":"Familial Addison\u2019s disease; 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